3-oxo-1-oxa-4,8-diazaspiro(4.5)decanes

ABSTRACT

3-OXO-1-OXA-4,8-DIAZASPIRO(4.5)DECANES HAVING THE GENERAL FORMULA   WHEREIN R, R1, R2, R3 and n are defined hereinafter, their pharmaceutically acceptable acid addition salts thereof and methods for the preparation of said compounds are disclosed. The compounds are used as agents having strong reserpine antagonistic activity and agents for lowering the blood sugar level.

ite

States atent Naltanishi et al.

3-OXO-1-OXA-4,8- DIAZASPIRO(4.S)DECANES Inventors: Michio Nakanishi, Oita; Katsuo Arimura, Fukuoka; Hideki A0, Oita, all of Japan Yoshitomi Pharmaceutical Industries, Ltd., Osaka, Japan Filed: Dec. 31, 1970 Appl. No.: 103,322

Assignee:

References Cited UNITED STATES PATENTS 12/1969 Loev ..260/294.7

3,574,204 4/1971 Nakanishi et al ..26()/243 Primary ExaminerHenry R. Jiles Assistant Examiner-G. Thomas Todd Att0meySughrue, Rothwell, Mion, Zinn & Macpeak [57] ABSTRACT 3-oxol -oxa-4,8-diazaspiro[ 4.5 ]decanes general formula having the wherein R, R, R R and n are defined hereinafter, their pharmaceutically acceptable acid addition salts thereof and methods for the preparation of said compounds are disclosed. The compounds are used as agents having strong reserpine antagonistic activity and agents for lowering the blood sugar level.

7 Claims, No Drawings 3-OX0- l -XA-4,8-DIAZASPIRO(4 .5)DECANES SUMMARY OF THE INVENTION This invention relates to novel and therapeutically or the pha'rmaceutically acceptable acid addition salts thereof, wherein R is H, acetyl, allyl, 2-propynyl, 2- cyanoethyl, C alkyl (for example, methyl, ethyl, propyl or butyl), C alkoxycarbonyl, C alkoxycarbonylethyl, benzoyl, benzyl or phenethyl, each of R and R is H, methyl, ethyl or phenyl, R is H, C alkyl, benzyl, phenyl or substituted phenyl, the substituent being selected from the group consisting of Cl, CH CH O or CF and n is 0 or 1.

DETAILED DESCRIPTION OF THE INVENTION The compounds (I) can be produced by the following methods:

i. By the reaction of a compound of the formula or a salt thereof such as a hydrochloride with a compound of the formula The reaction is usually carried out in a solvent such as benzene, toluene, xylene or dioxane in the presence of an acid catalyst such as p-toluenesulfonic, benzenesulfonic, sulfuric or phosphoric acid at refluxing temperatures to remove the water formed, or in a solvent such as ethanol, chloroform, tetrahydrofuran, benzene, toluene or xylene in the presence of a dehydrating agent such as calcium oxide, anhydrous magnesium sulfate, anhydrous zinc chloride, molecular sieves or N,N'- dicyclohexylcarbodiimide at room temperature or at an elevated temperature;

ii. By the reaction of a compound of formula (II) or a salt thereof with a compound of the formula HOC(R) (R (CH -COOH iv and a compound of the formula R3NH2 (v) or a salt thereof, for example, ammonium carbonate.

The reaction is usually carried out in a solvent such as benzene, toluene, xylene, chloroform or ethanol in the presence of an acid catalyst such as p-toluenesulfonic, benzenesulfonic, hydrochloric or sulfuric acid for several to several tens of hours while removing the water formed.

In this reaction, an intermediate having the following formula (VI) is firstly formed by the reaction of compound (II) with compound (V).

RN -N R= The intermediate (VI) can be separated and then subjected to the next reaction, i.e., reaction with compound (IV). The separation, however, is not always necessary.

iii. By the reaction of a compound of the formula OC(R1)(R2) HN\ (0112),. NC=O with a compound of the formula Y (Vlll) wherein R is acetyl, allyl 2-propynyl, 2-cyanoethyl, C alkyl, C alkoxycarbonyl, C alkoxycarbonylethyl, benzyol, benzyl or phenethyl, and Y is a halogen atom or a reactive radical such as methylsulfonyloxy or p-tolyl sulfonyloxy.

The reaction is usually carried out in a solvent such as ethanol, dimethylformamide, acetone, benzene, toluene, xylene, ethyl acetate, tetrahydrofuran or dioxane in the presence of an alkalizing agent such as an alkali metal carbonate, an alkali metal hydrogen carbonate, an alkali metal hydroxide, and alkali metal alkoxide, triethylamine, diethylaniline, dimethylaniline or pyridine at refluxing temperatures for several to several tens of hours.

The compounds (I) where R is H are produced also by the following method: iv. By the removal of the R" group of compounds of the formula wherein R" is benzyl or C alkoxycarbonyl.

The removal of the benzyl group is carried out by subjecting compound (IX) (R being benzyl) to catalytic reduction using a catalyst such as palladium charcoal, palladium oxide or Raney-nickel in a solvent such as water, methanol, ethanol, isopropanol, dioxane or acetic acid under normal or increased pressure at room temperature to about C for from 1 to 20 hours.

The removal of C alkoxycarbonyl is carried out by treating compound (IX) (R" being C alkoxycarbonyl) with an acid such as hydrogen chloride, hydrogen bromide, hydrogen fluoride, perchloric acid or trifluoroacetic acid in a solvent, especially with from 10 to 20 percent hydrogen bromide in acetic acid, the decomposition of the spiro ring being avoided under anhydrous conditions, or with an alkali such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide or magnesium hydroxide in a sol- .tion as shown, for example, by the following tests.

Compound Reserpine Antagonistic Activity RD mg/kg The compounds A-F above are shown below:

A: 2-Methyl-3-oxo-l-oxa-4,8-diazaspiro[4.5]decane Hydrochloride B: 3-Oxo-2-phenyl-l-oxa-4,8-diazaspiro[4.5]decane Hydrobromide 8-Ethyoxycarbonyl-2-methyl'3-oxo-1-oxa-4,8-

diazaspiro[4.5]decane D: 2-Methyl-3-oxo-8-phenethyl-l-oxa-4,8-

diazaspiro[4.5 ]decane Hydrochloride 8-Benzoyl-2-methyl-3-oxo-1-oxa-4,8-

diazaspiro[4.5]decane F: 8-(2-Cyanoethyl)-2-methyl-3-oxo-l-oxa-4,8-

diazaspiro[4.5]decane Maleate 2. Blood Sugar Lowering ACtion in Glucose Fed Mice The test compound (2-methyl-3-oxo-l-oxa-4,8- diazaspiro [4.51decane) was administered orally to ddstrain mice (female, 20-25 g) starved overnight. One hour later 4 g per kg of body weight of glucose was administered orally to the mice and, after one additional hour, the blood sugar value was measured. The ED value [dose required to lower the blood sugar level by 20 percent against the glucose fed mice (control)] was 5 mg/kg.

In view of various tests including those described above, the compounds (I) of the invention and their salts can be administered safely for the treatment of mania, diabetes and prediabetes, in the form of a pharmaceutical preparation with a suitable and conventional carrieror adjuvant, administerable orally or by way of injection, without harm to the patients.

The pharmaceutical preparations can take any conventional form such as tablets, capsules, granules, powder, syrups, injectable solutions and the like.

FORMULATION EXAMPLE 25 mg and 50 mg tablets are prepared from the following composition:

25 mg Tablets 50 mg Tablets Compound (1) 25 mg 50 mg Lactose mg 65 mg Microcrystalline Cellulose 15 mg 17 mg Starch l8 mg 15 mg Methylcellulose l mg 1.5 mg Magnesium Stearate 1 mg 1.5 mg

l30 mg 150 mg The oral daily dose of Compound (I) or a salt thereof for human adults usually ranges from about 50 to 300 milligrams, in single or multiple doses.

In the following illustrative examples of typical and presently preferred embodiments of the invention, g and ml" represent gram(s)" and milliliter(s), respectively.

EXAMPLE l A solution of 10 g of 1-ethoxycarbonyl-4-piperidone, 5.4 g of lactamide and l ml of concentrated sulfuric acid in 200 ml of benzene is heated under reflux in a flask provided with a water-removing apparatus for 16 hours. After cooling, the reaction mixture is washed twice with 30 ml of about 10 percent aqueous sodium hydrogen sulfite solution and then with water. The mixture is dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The yellow-brown residue thus obtained in recrystallized from a mixture of benzene and ligroin to give 3.1 g of white crystalline 8-ethoxycarbonyl-2-methyl-3-oxo- 1 -oxa-4,8-diazaspiro[4.5 ]decane melting at l03-105C.

EXAMPLE2 A solution of g of l-ethoxycarbonyl-4- piperidone, 71 g of dl-mandelamide and l g of ptoluenesulfonic acid in 700 ml of toluene is heated under reflux with stirring in a flask provided with a water-removing apparatus for 12 hours. After cooling, the reaction mixture is washed twice with water, dried overanhydrous sodium sulfate, and the solvent is distilledoff under reduced pressure. The dark brown jelly-like residue solidifies on cooling. The solid is washed with a small amount of isopropanol and recrystallized from isopropanol to give g of white crystalline 8-ethoxycarbonyl-3-oxo-2-phenyl-l-oxa- 4,8-diazaspiro[4.5]decane melting at l40-141C.

EXAMPLE 3 A mixture of 12.5 g of 3-oxo-2-phenyl-1-oxa-4,8- diazaspiro[4.5]decane hydrobromide, 7 g of butyl bromide, 10 g of potassium carbonate, ml of dimethylformamide and 30 ml of ethanol is heated under reflux with stirring for 6 hours. After cooling, the insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The solid thus obtained is washed with water and recrystallized from isopropanol to give 10 g of white crystalline 8-butyl-3-oxo-2-phenyl-1-oxa-4,8-diazaspiro[4.5]decane melting at 146C. Its maleate melts at 206-207C.

l-oxa-4,8-diazaspiro[4.5 ]decane EXAMPLE 4 Benzoyl chloride (5.1 g) is added portionwise to a mixture of 7.5 g of 2methyl-3-oxo-l-oxa-4,8- diazapiro[4.5]decane hydrochloride, 7 g of potassium carbonate, 50 ml of dimethylformamide and 50 ml of toluene. The resulting mixture isstirred at room temperature for 1 hour and then heated under reflux for 9 hours. After cooling, the insoluble matter is filtered off and the filtrate is concentrated under reduced pressure. The residue is dissolved in chloroform, the solution is washed twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, the chloroform is distilled off, and the pale brown solid thus obtained is recrystallized twice from toluene to give 6 g of white crystalline 8-benzoyl-2-methyl-3-oxomelting at l75l76C.

EXAMPLE 5 To a solution of g of 8-benzyl-2-methyl-3-oxo-loxa-4,8-diazaspiro[4.5 ]decane in 120 ml of 50 percent ethanol containing 10 ml of concentrated hydrochloric acid is added 3 g of 10 percent palladium charcoal and the resulting mixture is reduced under normal pressure at room temperature until the absorption of hydrogen stops. After the reduction, the palladium charcoal is filtered off, and the filtrate is concentrated under reduced pressure. The white crystals thus obtained are recrystallized from ethanol to give 4 g of white crystal line 2-methyl-3-oxo-1-oxa-4,8-diazaspiro[4.5]decane hydrochloride melting at 240C.

EXAMPLE 6 To a solution of g of 8-benzyl-4-butyl-2-methyl-3- oxo-l -oxa-4,8-diazaspiro[4.5 ]decane hydrochloride in 250 ml of 50 percent ethanol is added 6 g of 5 percent palladium charcoal, the resulting mixture is placed in an autoclave, the autoclave is charged with hydrogen at 80 atmospheres, and then the reduction is carried out at 60C for 1 hour. After cooling, the palladium charcoal is filtered off, water is added to the filtrate, and the aqueous solution is made alkaline with potassium carbonate. The oil separated is extracted with chloroform, the extract is washed with water, dried over magnesium sulfate, and the chloroform is distilled off. The pale yellow viscous oil (7.5 g) thus obtained is dissolved in 30 ml of ethanol, and 3.9 g of maleic acid is added to the solution. After cooling, the crystals precipitated are separated and recrystallized from ethanol to give 5 g of white crystalline 4-butyl-2-methyl-3-oxo-l-oxa-4,8- diazaspiro[4.5]decane maleate melting at 175-] 76C.

EXAMPLE 7 A mixture of 10 g of 4-p-chlorophenyl-2,2-dimethyl- S-ethoxycarbonyl-B-oxol -oxa-4,8- diazaspiro[4.5]decane and 100 ml of percent solution of hydrogen bromide in acetic acid is heated on a water bath for 3 hours. After cooling, the acetic acid is distilled off under reduced pressure and the solid thus obtained is recrystallized from ethanol to give 6.5 g of white crystalline 4-p-chlorophenyl-2,2-dimethyl-3-oxo- 1-oxa-4,8-diazaspiro[4.5]decane hydrobromide melting at 320-321C with decomposition.

EXAMPLE 8 A mixture of l0 g of 4-p-chlorophenyl-2,Z-dimethyl- 8-ethoxycarbonyl-3-oxol -oxa-4,8- diazaspiro[4.5]decane, 15 g of barium hydroxide octahydrate and ml of ethylene glycol is heated under reflux with stirring for 16 hours. After cooling, the insoluble matter is filtered off, water is added to the filtrate, and the resulting solution is extracted three times with chloroform. The combined extract layer is washed three times with water and dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The pale brown solid thus obtained is recrystallized from toluene to give 4.5 g of white crystalline 4-pchlorophenyl-2,2-dimethyl-3-oxo-l-oxa-4-,8- diazaspiro [4.5 ]decane melting at l4l-l 42C.

EXAMPLE 9 A mixture of 77 g of l-ethoxycarbonyl-4-piperidone,

56.5 g of p-chloroaniline, 0.5 g of p-toluenesulfonic acid and 400 ml of toluene is heated under reflux with stirring in a flask provided with a water-removing apparatus for 9 hours. After cooling to room temperature, 50 g of oz-hydroxy-isobutyric acid is added, and the mixture is heated under reflux for 9 additional hours. After cooling, the reaction mixture is washed successively with water, aqueous sodium carbonate, water, diluted hydrochloric acid, water, acqueous sodium hydrogen sulflte and water, and dried over anhydrous magnesium sulfate. Then the toluene is distilled off. The brown solid thus obtained is washed with isopropyl ether and recrystallized from ethanol to give white crystalline 4-p-chlorophenyl-2,2-dimethyl-8-ethoxycarbonyl-3 -oxol -oxa-4,8-diazaspiro[4.5 ]decane melting at 206207C EXAMPLE 10 A mixture of 85.5 g of l-ethoxycarbonyl-4- piperidone, 54 g of lactic acid, 65.5 g of ammonium carbonate, 0.5 g of p-toluenesulfonic acid and 500 ml of toluene is heated under reflux in a flask provided with a water-removing apparatus for 16 hours. After cooling, the reaction mixture is washed successively with water, aqueous sodium hydrogen carbonate, water, diluted hydrochloric acid, water, aqueous sodium hydrogen sulfite and water, and dried over anhydrous magnesium sulfate. Then the toluene is distilled off. To the brown jelly-like residue is added isopropyl ether and crystallization is induced by scratching the flask. The crystals are collected by filtration and recrystallized from isopropyl ether to give white crystalline 8-ethoxy-carbonyl-2-methyl-3-oxo-loxa-4,8-diazaspiro[4.5]decane melting at l07-l08C.

Using the procedures set forth in above examples, but substituting equivalent amounts of the appropriate starting materials, the following compounds are also produced:

1. 3-Oxol -oxa-4,8-diazaspiro[4.5 ]decane, hydrobromide melting at 231-232C;

2. 3-Oxo 4-m-trifluoromethylphenyl-l-oxa-4,8- diazaspiro[4.5 ]-decane, its maleate melting at 215C;

3. 2,4-Dimethyl-3-oxo-l -oxa-4 ,8- diazaspiro[4.5]decane, its hydrobromide melting at 2l5-216C;

its

l l. 4-Oxo-2-phenyl-1-oxa-5 ,9-diazaspiro[5.5 ]undecane, its hydrochloride melting at 242C with decomposition;

l2. 2,2-Dimethyl-3-oxo-l-oxa-4,8- diazaspiro[4.5]decane, its hydrobromide melting at 283C with decomposition;

l3. 2-Methyl-3-oxo-2phenyl-l-oxa-4,8-

diazaspiro[4.5 ]decane melting at 227C;

14. 2,2-Diphenyl-3-oxo- 1 -oxa-4,8- diazaspiro[4.5 ]decane melting at 2l4-2 l 5C;

15. 4-Butyl-2,2-diphenyl-3-oxol -oxa-4,8- diazaspiro[4.5]decane, its maleate melting at 176-l77C;

l6. 8-Methyl-3 -oxo-2-phenyll -oxa-4,8-

diazaspiro[4.5]decane melting at 188-189C, and its maleate melting at 222C;

17. 2,8-Dimethyl-3-oxo-l-oxa-4,8- diazaspiro[4.5 ]decane, its maleate melting at 207C;

18. 8-Butyl-2-methyl-3-oxol -oxa-4,8- diazaspiro[4.5 ]decane, its hydrochloride melting at 256C with decomposition;

19. 8-Acetyl-2-methyl-3-oxo-1-oxa-4,8- diazaspiro[4.5]decane melting at 154155C;

20. 8-Acetyl-2,2-diphenyl-3oxo-l-oxa-4,8- diazaspiro[4.5 ]decane melting at 247C;

21. 8-Allyl-2-methyl-3-oxol -oxa-4,8- diazaspiro[4.5 ]decane its maleate melting at 155C;

22. 2-Methyl-3-oxo-8-(2-propynyl)-l-oxa-4,8- diazaspiro[4.5 l-decane, its maleate melting at 162163C;

23. 8-(2-Cyanoethyl)-2-methyl-3-oxol -oxa-4,8- diazaspiro[4.5]decane, its maleate melting at 195C;

24. 8-Ethoxycarbonyl-3-oxo-l-oxa-4,8- diazaspiro[4.5 ]decane melting at 99-100C;

25. 8-Ethoxycarbonyl-2-ethyl-3-oxo-1-oxa-4,8- diazaspiro[4.5 ]decane melting at 99-10 1C;

26. 2,2-Diphenyl-8-ethoxycarbonyl-3-oxo-l-oxa-4,8- diazaspiro[4.5]decane melting at l74l 75C;

27. 8-Ethoxycarbonyl-2-methyl-3-oxo-2-phenyl-1- oxa-4,8-diazaspiro[4.5 ]decane melting at l17-1 18C;

28. 2,2-Dimethyl-8-ethoxycarbonyl-3-oxo-l-oxa- 4,8-diazaspiro[4.5 ]decane melting at 186C;

29. 4-Butyl-8-ethoxycarbonyl-2-methyl-3-oxo-l-oxa- 4,8-diazaspiro[4.5]decane showing n 1.4660 (colorless liquid);

30. 2,4-Dimethyl-8-ethoxycarbonyl-3-oxo-l-oxa- 4,8-diazaspiro[4.5 ]decane melting at 70-72C;

31. 9-Ethoxycarbonyl-4-oxo-2-phenyll -oxa-5 ,9- diazaspiro[5.5]-undecane melting at l77-l78C-,

32. 8-(2-Methoxycarbonylethyl)-2-methyl-3-oxo-loxa-4,8-diazaspiro[4.5]decane its maleate melting at l37-139C;

33. 8-Benzoyl-3-0xo-2-phenyl-l-oxa-4,8- diazaspiro[4.5 ]decane melting at l96-l97C;

34. 8-Benzyl-2-methyl-3-oxo-1-oxa-4,8- diazaspiro[4.5]decane, its hydrochloride melting at 251C;

35. 8-Benzyl-2,2-diphenyl-3 -oxo-l -oxa-4,8- diazaspiro[4.5 ]decane melting at 205C;

36. 8-Benzyl-3-oxo-2-phenyl-l -oxa-4,8- diazaspiro[4.5]decane, its maleate melting at 234C with decomposition;

37. S-Benzyl-4-p-chlorophenyl-2,2-dimethyl-3-oxol-oxa-4,8-diazaspiro[4.5 ]decane melting at 168-1 69C;

3 8. 9-Benzyl-4-oxo-2-phenyl-1-oxa-5 ,9-

diazaspiro[5.5 ]undecane melting at l89l C;

39. 2-Methyl-3-oxo-8-phenethyl-l -oxa-4,8- diazaspiro[4.5 ]decane, its hydrochloride melting at 265C with decomposition;

40. 3-Oxo-8-phenethyl-2-phenyl-l-oxa-4,8- diazaspiro[4.5 ]decane, its hydrochloride melting at 233234C.

What is claimed is:

l. A compound selected from the group consisting of those of the forumula wherein R is selected from the group consisting of a hydrogen atom, an acetyl group, an allyl group, a 2- propynyl group, a 2-cyanoethyl group, an alkyl group having from one to four carbon atoms, an alkoxycarbonyl group, said alkoxy group having from one to four carbon atoms, an alkoxycarbonylethyl group, said alkoxy group having from one to four carbon atoms, a benzoyl group, a benzyl group and a phenethyl group, wherein each of R and R is selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group and a phenyl group, wherein R is selected from the group consisting of a hydrogen atom, an alkyl group having from one to four carbon atoms, a benzyl group, a phenyl group and a substituted phenyl group, said substituent being selected from the group consisting of Cl, CH CH O and CH, and wherein n is Oor l; and the pharmaceutically acceptable acid addition salts thereof.

2. The compound of claim 1, wherein said compound is 2-methyl-3-oxo-1-0xa-4,8-diazaspiro[4.5 ]decane.

3. The compound of claim 1, wherein said compound is 3-0x0-2-phenyll -oxa-4,8-diazaspiro[4.5 ]decane.

4. The compound of claim 1, wherein said compound is 8-ethoxy-carbonyl-2-methyl-3-oxo-1 -oxa-4,8- diazaspiro[4.5]decane.

5. The compound of claim 1, wherein said compound is 2-methyl-3 -oxo-8-phenethyll -oxa-4 ,8- diazaspiro[4.5]decane.

6. Th compound of claim 1, wherein said compound is 8-benzoyl-2-methyl-3-oxol -oxa-4 ,8- diazaspiro[ 4.5 Idecane.

7Q The compound of claim 1, wherein said compound is 8-(2-cyanoctl1yl)-2-methyl-3-oxo-l-oxa-4,8- diazaspiro[4.5 ]decanc. 

2. The compound of claim 1, wherein said compound is 2-methyl-3-oxo-1-oxa-4,8-diazaspiro(4.5)decane.
 3. The compound of claim 1, wherein said compound is 3-oxo-2-phenyl-1-oxa-4,8-diazaspiro(4.5)decane.
 4. The compound of claim 1, wherein said compound is 8-ethoxy-carbonyl-2-methyl-3-oxo-1-oxa-4,8-diazaspiro(4.5)decane.
 5. The compound of claim 1, wherein said compound is 2-methyl-3-oxo-8-phenethyl-1-oxa-4,8-diazaspiro(4.5)decane.
 6. The compound of claim 1, wherein said compound is 8-benzoyl-2-methyl-3-oxo-1-oxa-4,8-diazaspiro(4.5)decane.
 7. The compound of claim 1, wherein said compound is 8-(2-cyanoethyl)-2-methyl-3-oxo-1-oxa-4,8-diazaspiro(4.5)decane. 